RNA construct and methods of use thereof for enhancing the therapeutic effects of cytotoxic cells and stem cells
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Publication Number
US-12128061-B2
Publication Date
2024-10-29
Expiration Date
Abstract
The present invention comprises Rig I agonists for enhancing the effects of cytotoxic cells and stem Cells. The Rig I agonists can be used in vivo as small molecule therapeutics or in vitro to enhance cells for adoptive cell transfer. Applications include cancer therapy, immune system enhancement, chronic viral infection and treatment of viral induced inflammation and enhancement of virus based therapies.
Core Innovation
The invention concerns a Rig I agonist comprising an RNA molecule having a central hairpin and an internal loop, wherein the RNA molecule comprises SEQ ID NO 1. When administered, the RNA molecule produces no interferon response and does not induce type I interferon response, including IFN-α and IFN-β, unlike prior examples.
The described RIG-I agonist RNA construct is associated with enhanced cytotoxic cell functions, including increased granzyme B and perforin loads. The disclosed activity is described across cytotoxic cell types including NK cells, CD8 T cells, and stem-cell populations, with improved viability and serial killing.
The invention is also described in connection with cancer therapy and chronic viral infection/inflammation, including Hepatitis C and HIV, and with enhancing in vivo oncolytic virus therapies. The disclosed uses include immune-related strategies in the tumor microenvironment and combinations that may involve immune checkpoint inhibitors and killer-cell engagers (BIKEs/TRIKEs), as well as delivery concepts such as adoptive cell transfer and extracellular vesicle/exosome or RNA nanoparticle delivery.
Claims Coverage
Two independent claims are provided, covering a Rig I agonist RNA molecule that produces no interferon response and an isolated cytotoxic cell that contains at least one SEQ ID NO:1 RNA molecule. The coverage is anchored around the structural RNA features (central hairpin and internal loop) and the absence of interferon response, and extends the same SEQ ID NO:1 RNA into the definition of an isolated cytotoxic cell.
Rig I agonist with central hairpin and internal loop and no interferon response
A Rig I agonist comprising an RNA molecule having a central hairpin and an internal loop, and which produces no interferon response when administered, wherein the RNA molecule comprises SEQ ID NO 1.
Isolated cytotoxic cell containing SEQ ID NO: 1 RNA
An isolated cytotoxic cell comprising at least one RNA molecule comprising SEQ ID NO: 1.
Overall, the claim coverage centers on SEQ ID NO:1 as a Rig I agonist RNA defined by a central hairpin and internal loop that produces no interferon response when administered, and on isolated cytotoxic cells that include at least one such SEQ ID NO:1 RNA molecule.
Stated Advantages
Produces no interferon response when administered.
Increases granzyme B and perforin loads in cytotoxic cells.
Improves viability and serial killing for NK cells, CD8 T cells, and stem-cell populations.
Does not induce type I interferon response (IFN-α/IFN-β), unlike prior Rig I agonists (M5 and M8).
Documented Applications
Cancer therapy, including enhancement of in vivo oncolytic virus therapies.
Chronic viral infection/inflammation, including Hepatitis C and HIV.
Immune response enhancement in the tumor microenvironment.
Use involving adoptive cell transfer, including administering a patient a cell treated with the Rig I agonist of claim 1.
Combination concepts in the tumor microenvironment, including co-administering the Rig I agonist together with at least one of BIKEs, TRIKEs, or a monoclonal antibody.
Delivery in the context of immune boosting using targeted oncolytic viruses, viral vectors, monoclonal antibodies, ferried and/or cell-penetrating peptides, or extracellular vesicles derived from Rig I agonist-transfected cells.
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